The $60,000 research grants were awarded to support an important area in which more scientific investigation is needed to identify the earliest precursors of Alzheimer’s disease. The award provides a broad array of funding for research that investigates the causes and progression of Alzheimer’s, including the basic mechanisms of aging, genetics, biomarkers, inflammation, and the impact of exercise and the environment.

2008 Award Recipients:

Christopher Conrad, PhD
Assistant Professor
Columbia University
RNAi and Genetic Linkage of AD

Current methods for discovering genes associated with Alzheimer's disease often require years of verification. Dr. Conrad hopes that by using cellular models, he can come up with a way to more quickly identify promising genes for further, in-depth study. He is focusing on 31 genes, all expressed in the brain, in a recently identified region on chromosome 3, 3q28, which is associated with late onset Alzheimer's disease. By eliminating each gene, he can see what impact that has on cellular models of Alzheimer's disease. "Our project will investigate whether our method will accelerate the identification of Alzheimer's disease-associated genes," he said.

Koichi Iijima, PhD
Assistant Professor
Thomas Jefferson University
The Role of Histone Modifications in Alzheimer’s Amyloid-Beta42-induced Neurotoxicity inVivo

Abnormal accumulation of a peptide composed of 42 amino acids, called amyloid-beta, in the brain is suspected of playing a central role in the development of Alzheimer’s disease. However, it remains unclear how amyloid-beta causes dysfunction and degeneration. De-acetylated histone proteins tightly package DNA. Regions of tightly packaged DNA are called heterochromatin; there is limited transcription of genes in these areas. In Alzheimer-affected brains, heterochromatin formation is increased. But, Dr. Iijima said, it is “not understood whether these changes are a cause or a mere consequence” of the disease. Using a genetically altered fruit fly carrying human amyloid-beta, Dr. Iijima found that histone acetylation levels were reduced in the fly brains. In addition, inhibiting the function of histone acetyltransferase (HDAC) complex appeared to protect against amyloid-beta induced dysfunction. The study “may encourage the exploration in the application of inhibitors of HDAC complex as a potential therapy” for Alzheimer’s disease,” Dr. Iijima said.

Suman Jayadev, MD
Acting Assistant Professor
University of Washington
Presenilin-2 Mutations and Microglia Function in Alzheimer’s Disease

Inflammation in the brain has been implicated in the development of Alzheimer’s disease. Dr. Jayadev hopes to understand how this inflammation causes or worsens degeneration in Alzheimer’s disease by introducing Presenilin-2 mutations into brain immune cells, or microglia. Her goal is to understand how Presenilin-2 may contribute to that degeneration. Presenilin-2 mutations have been shown to cause familial Alzheimer’s disease. She then will assess the impact of these mutations on the normal functions of the microglia. “Characterizing this novel role for presenilin and describing its function and dysfunction may reveal additional and perhaps more specific targets for drug therapies,” Dr. Jayadev said.

Ling Qi, PhD
Assistant Professor
Cornell University
Manipulation of Unfolded Protein Response in Neurodegeneration

Both Alzheimer’s and Parkinson’s diseases share a common pathology: accumulation of insoluble, misfolded protein deposits. Dr. Qi’s research focuses at the genetic level on defense mechanisms in the brain that might prevent the accumulation of those deposits, also known as unfolded protein response (UPR). Specifically, he is looking at whether enzymes, histone acetylases CBP/P300, can activate a key protein in UPR, XBP1. XBP1 is known to control many components of protein folding and degradation. Thus, it may be capable of preventing the accumulation of protein aggregates and, ultimately, the death of neurons. This one day could lead to gene therapy, he said. "Genetic regulation is very complex," he said. "This is the very first step to understand the transcription event occurring during UPR. It can lead to future investigations so that we may get closer and closer to understanding these diseases."

Inna Slutsky, PhD
Lecturer
Tel Aviv University
Initiation of Alzheimer's Disease: From Inhibition of Neprilysin Activity to Temporal Code at Individual Hippocampal Synapses

A loss with age of neprilysin, an enzyme participating in the clearance of beta amyloid peptides in the brain, has been proposed to cause the cognitive impairments in common, late-onset Alzheimer's disease. "The mechanisms transforming neprilysin deficiency to synapse loss in AD subjects remain obscure," she said. Synapse loss is the most obvious physical sign of memory loss in Alzheimer patients. Dr. Slutsky hopes to determine how neuronal activity regulates neprilysin expression, release of beta amyloid peptides and the number of functional synapses in physiological and pathological conditions. She will use high-resolution optical imaging that can look at individual synapses in hippocampal neurons and electrophysiology that can monitor neuronal connections. "Understanding the physiological functions of neprilysin and amyloid beta peptides is crucial for targeting the early synaptic dysfunctions to prevent synapse loss and memory decline in AD," she said.

Alzheimer's disease is the most prevalent neurodegenerative disease affecting an estimated 26 million people worldwide, including 4.5 million Americans. Scientists predict that the prevalence of the disease will double for every five-year age group beyond 65. With the growing aging population, Alzheimer's will have an enormous health, societal, and cost impact.

"We are pleased that The Rosalinde and Arthur Gilbert Foundation has once again made an investment in research that will continue to enhance our knowledge about the aging brain and how genes, environmental factors, and chance events influence the incidence and progression of Alzheimer's disease," said George M. Martin, MD, Director Emeritus, Alzheimer's Disease Research Center, University of Washington School of Medicine and Scientific Director of the American Federation for Aging Research. "Through their generous contribution - now supporting 11 researchers since the program's inception -- the next generation of scientists will continue the progress made in Alzheimer's research allowing us the opportunity to intervene and prevent or possibly cure the disease," he added.

"The Rosalinde and Arthur Gilbert Foundation has invested in an outstanding group of U.S. and Israeli researchers who have the potential to make important and lasting contributions to Alzheimer's disease and aging science," said Martin H. Blank, Jr., co-director and Chief Operating Officer of the Foundation.

About the Rosalinde and Arthur Gilbert Foundation
The Rosalinde and Arthur Gilbert Foundation (www.thegilbertfoundation.org) invests in programs in the areas of College Access, Healthcare and Israel. In addition, The Foundation funds Arts Education & Culture in Los Angeles, Jewish Programs in Los Angeles, and Universities in California. In the area of Alzheimer’s disease, The Rosalinde and Arthur Gilbert Foundation focuses its grantmaking on the advancement of research by junior investigators in the United States and Israel and investments in Alzheimer’s disease caregiving.

The American Federation for Aging Research is a nonprofit organization whose mission is to support biomedical research on aging. It is devoted to creating the knowledge that all of us need to live healthy, productive, and independent lives. Since 1981, AFAR has awarded more than $113 million to nearly 2,500 talented scientists as part of its broad-based series of grant programs. Its work has led to significant advances in our understanding of the aging process, age-related diseases, and healthy aging practices. AFAR communicates news of these innovations through its organizational web site www.afar.org and educational web sites Infoaging (www.infoaging.org) and Health Compass (www.healthcompass.org).